Project Summary The novel NAD glycohydrolase, SARM1, is an active executioner in progressive axonal and neuronal degeneration1. This type of degeneration, termed Wallerian degeneration, defines a number of diseases, including neuropathies, traumatic brain injury and neurodegenerative diseases, yet no therapies exist. In fact, prior to the discovery of SARM1?s role in triggering Wallerian degeneration, the process was believed to occur passively. SARM1?s causal role in Wallerian degeneration demonstrates that it is an attractive therapeutic target that could prevent disease progression. However, the design of therapeutics targeting SARM1 is limited by the dearth of knowledge surrounding its inherent NADase activity. In order to evaluate SARM1?s therapeutic efficacy and design potential SARM1 inhibitors, the proposed research will study its structure, enzymatic mechanism and cellular activity. Solving the structure by leveraging the benefits of crystallography and cryoEM, determining the enzymatic mechanism via a series of assays and analyzing the in vivo activity with activity-based probes will fill in important gaps. Revealing these properties would enable the design of SARM1 inhibitors that could ultimately treat Wallerian-type diseases. Moreover, demystifying the role SARM1 plays in neurodegeneration would also allow for a better understanding of these disease types, the enzymatic capabilities of toll/interleukin receptor (TIR) domains and the involvement of NADases in numerous disease states.